Use of mirtazapine for the treatment of sleep disorders

ABSTRACT

The invention relates to the use of mirtazapine for the preparation of a medicine for a new method of treatment of a sleep disorder in a subject, which treatment comprises the administration of mirtazapine with a unit treatment dose comprising between 0.1 and 5 mg mirtazapine and relates to a patient pack for the treatment of sleep disorders.

FIELD OF THE INVENTION

The invention relates to the use of mirtazapine for the preparation of amedicine for a new method of treatment of a sleep disorder in a subject.

BACKGROUND OF THE INVENTION

Sleep difficulties are a major motivation for use of drugs. The mostoften selected drugs are those interacting with the GABAneurotransmitter-receptor system in the brain, the so-called minortranquillisers, of which the group of benzodiazepine drugs is theclassic example. Disadvantages of currently available hypnotics are thepotential for adverse reactions, remaining lesser quality of sleep,hangover effects, dependency potential, withdrawal effects andundesirable effects on cognitive functioning. The quality of sleep cannot only be derived from the effect of sleep, for example whether thesleep has been refreshing and has a positive effect on daytimedrowsiness/alertness the morning after, but also from objective EEGdetermined characteristics, describing sleep stages and architecture.

The discovery of different types of benzodiazepine receptors areexploited to open new avenues for pharmaco-therapy of insomnia (forreview see C. K. Kirkwood; Management of insomnia; J Am Pharmaceut. Ass.Vol 39 pp 688-696; 1999). Other mechanisms for inducing sleep are alsoexplored. The opiate-like drugs, the barbiturates and anti-histaminesare drug classes which have been used several decades ago as sleepinducers, but their use became obliterated due to undesirable sideeffects and/or lesser efficacy. Such drugs are still in use for otherdisorders whereby the main effects would be side effects when used forthe treatment of sleep disorders. Specifically, drugs, antagonisinghistamine receptors are sedative and sleep inducing but are not usedregularly anymore for the treatment of sleep disorders in view of lowerselectivity, lower potency and lower safety in comparison tobenzodiazepines and their modern successors.

Mirtazapine is known as an anti-depressant. It is active for thatpurpose at daily doses of 15-45 mg per person. It is well-known that thedose is crucial for effective therapy, in particular for the treatmentof depression. Mirtazapine is reported to have some initial sedativeeffects and because of this its effects on sleep have been investigated.It is reported that in the dose range of 5-30 mg per person per dayimprovement of transient, or situational insomnia is found, whereby thedose of 15 mg was reported to be preferable over 5 mg (Sørensen et al.Acta Psychiatr. Scand. 71: 339-346; 1985). Also Winokur (BiologicalPsychiatry 1998; 45(8S): p 106S) investigates 15 and 30 mg mirtazapinein depressed patients with prominent sleep related complaints andrecommends further investigation of these doses for treatment of sleepdisorders.

BRIEF SUMMARY OF THE INVENTION

It has now been found that mirtazapine can be used for the preparationof a medicine for the treatment of a sleep disorder in a subject, whichtreatment comprises the administration of mirtazapine with a unittreatment dose comprising more than 0.1 and less than 5 mg mirtazapine,which in other words is a unit treatment dose (within the range) between0.1 and 5 mg mirtazapine.

In general this amounts for an average human person to a treatment dosein the range between 0.005 and 0.07 mg/kg.

In contrast to the expectations, the favourable results which make thecompound available as a valid alternative for known drugs of choice forthe treatment of sleep disorders were obtained with treatment dosesbelow the dose range studied and recommended by Sørensen et al. andWinokur (cited above). At least for individual patients mirtazapine inthe above indicated dose range can be a better choice than a choice ofone of the known sleep improving drugs in view of a better quality ofsleep after treatment.

DETAILED DESCRIPTION OF THE INVENTION

The amounts of mirtazapine defined in this description refer to theamount of free base of mirtazapine. Mirtazapine contains a centre ofchirality and can exist as stereoisomers. The present invention includesthe aforementioned stereoisomers within its scope and each of theindividual (R) and (S) enantiomer and their salts, substantially free,i.e. associated with less than 5%, preferably less than 2%, inparticular less than 1% of the other enantiomer and mixtures of suchenantiomers in any proportions including racemic mixtures containingsubstantially equal amounts of the two enantiomers.

The subject amenable for a treatment made available by this inventioncan be an animal or a human person. This invention is preferably to beapplied for a mammal and more preferably for a human person. Men andwomen often respond differently to drug treatment and suffer differentlyin nature, frequency and severity from sleep disorders. Also, there aredifferences in treatment methods for persons with sleep problems amongdifferent age groups. The elderly, adolescents or postmenopausal agegroups have different needs for treatment. Certain aspects of sleepquality improvement are more important for different age groups orgender or different sleep disturbances. Such differential factors are tobe taken into account in selecting the treatment of this invention andin selecting the exact dose of mirtazapine for the treatment. The veryexact dose and regimen of mirtazapine administration will necessarilydepend on the needs of the individual subject to whom it is beingadministered in the form of a medicament and on the nature or needs ofthe sleep disorder and the judgement of the medical practitioner. Ingeneral, parenteral administration requires lower dosages than othermethods of administration which are more dependent upon absorption.However, the daily dosages are between 0.005 and 0.07 mg/kg body weightof the recipient. The recipient is the subject receiving the dose ofmirtazapine for treatment of a sleep disorder.

There are several types of sleep disorders in man, of which primaryinsomnia is the most common one and preferably selected to be treatedwith a low dose of mirtazapine according to this invention. Other sleepdisorders are for example transient sleep disorders and secondary sleepdisorders. The sleep disorders can be diagnosed according to thecriteria and methods outlined in the Diagnostic and Statistical Manualof Mental Disorders 4^(th) edition (DSM IV) published by the AmericanPsychiatric Association, Washington, D.C. (1994).

While it is possible to administer mirtazapine, or a pharmaceuticalacceptable acid addition salt or solvate thereof, alone it is preferableto present it as a pharmaceutical composition adapted for the treatmentof sleep disorders, comprising the mirtazapine, or a pharmaceuticallyacceptable acid addition salt or solvate thereof, mixed with one or morepharmaceutically acceptable auxiliaries. The medicament comprisingmirtazapine may be administered enterally (e.g. orally, rectal nasal ortopically) or parenterally (e.g. via intramuscular, subcutaneous,intravenous or intraperitoneal injections).

A unit treatment dose (=a dosing unit) is an amount of mirtazapine in apharmaceutical presentation form for administration to a subject at aparticular point in time. A daily treatment dose can be administered inone or more dosage units suitable for example for the oral, the rectal,the sublingual or the nasal route or through the skin (for example,transdermal patches, or in the form of a cream).

The invention further includes a patient pack for treatment of sleepdisorders comprising dose units in combination with packaging materialsuitable for said dose units, whereby the dose units comprisepharmaceutical auxiliaries and mirtazapine in an amount between 0.1 and5 mg and optionally, said packaging material is including means to helpa recipient using the dose units most suitably for the treatment of asleep disorder. Such means to help a recipient using the dose units mostsuitably for the treatment as described before herein are, for example,instructions for the use of the composition. In such a patient pack theintended use of a formulation comprising mirtazapine for the treatmentof sleep disorders can be inferred by instructions, facilities,provisions, adaptations and/or other means to help using the formulationmost suitably for the treatment. Such measures make a patient packspecifically suitable for and adapted for use for treatment of a sleepdisorder.

For making means of dosing, such as pills, tablets, suppositories,(micro-)capsules, powders, emulsions, creams, ointments, implants, apatch, a gel, and any other preparation for sustained release, sprays,injection preparations in the form of a solution or suspension, suitableauxiliaries such as carriers, fillers, binders, lubricants, dispersants,emulsifiers, stabilisers, surfactants, anti-oxidants, colorants,preservatives and the like can be used e.g. as described in the standardreference, Gennaro et al., Remington's Pharmaceutical Sciences, (18thed., Mack Publishing Company, 1990, see especially Part 8:Pharmaceutical Preparations and Their Manufacture). In general anypharmaceutically acceptable auxiliary which does not interfere with thefunction of the active compounds is suitable and can be used.

Suitable fillers or carriers with which the compositions can beadministered include agar, alcohol, fats, lactose, starch, cellulosederivatives, polysaccharides, polyvinylpyrrolidone, silica, sterilesaline and the like, or mixtures thereof used in suitable amounts.

Binders are agents used to impart cohesive properties to apharmaceutical composition resulting in minimal loss from thepharmaceutical composition during production and handling. Binders arefor example cellulose, starches, polyvinylpyrrolidone, and the like.

A suitable lubricant with which the active agent of the invention can beadministered is, for example, magnesium stearate.

Surfactants are agents facilitating the contact and migration ofcompounds in different physical environments such as hydrophilic andhydrophobic environments. Many surfactants are known in the art ofmaking pharmaceutical compositions as for example described in chapter19 of Remington's Pharmaceutical Sciences (18th edition Editor A. R.Gennaro; Mack Publishing Comp; Easton, Pa.). Surfactants that can beused during the process of preparing the pharmaceutical formulation are,for example, polyethylene glycol (PEG), and the like.

Mirtazapine may be prepared using the method described in U.S. Pat. No.4,062,848 which is incorporated herein by reference.

The following example is an illustration of the use of mirtazapineaccording to the invention.

EXAMPLE

Mirtazapine is formulated in dosing units containing 0.5 mg, 1.5 mg and4.5 mg mirtazapine.

The dosing units containing 0.5 mg (as tablets) have the composition asindicated in table 1:

TABLE 1 Per tablet Per batch Tablet excipients in mg in gram Mirtazapine0.5 7.7 Cornstarch 6.5 100.0 Hydroxypropylcellulose 1.3 20.0 Magnesiumstearate 0.4875 7.5 Aerosil 0.975 15.0 Lactose 200 M to 65 mg to 1000gram

For preparation of tablets a 1000 g granulate batch with the compositionindicated in table 1 was prepared by premixing the complete amount ofmirtazapine (base) with 100 gram of lactose 200 M in a 1 liter glasscontainer for 10 minutes on a Turbula mixer at 22 rotations per minute(rpm). The mixture is sieved through a 150 μm sieve before and afterwhich a further 20 g of lactose 200 M is added. Granulation wasperformed in a high shear mixer granulator with the rest of the lactose,corn starch and hydroxypropyl-cellulose. The granulate was dried in atray vacuum cabinet, classified with a conical screen mill and mixedwith aerosil and magnesium stearate. The 65 mg tablets were compressedwith a diameter of 5 mm and a radius of convexity of 7.5 mm. Tabletswith 1.5 and 4.5 mg mirtazapine were prepared similarly whereby thequantity of lactose was adapted in order to compensate for the increasedquantity of mirtazapine.

Dosing units containing, 1.5 mg and 4.5 mg mirtazapine were preparedanalogously with compensatory reduction of the amount of lactose 200Mesh.

Effects of low dose mirtazapine on sleep in primary insomniac patients:a parallel double blind comparison with placebo and temazepam.

The study is a multi-centre study with participation of centres inseveral different countries in Europe.

Patients with primary insomnia are selected with diagnosis criteriaaccording to DSM IV. Furthermore, patients should have 2 out of thefollowing three objective characteristics: patients with sleep latency≧30 min, number of awakenings ≧3 per night, total sleep time ≦6,5 out of8 hours.

Major exclusion criteria are: secondary insomnia, sleep apnoea syndrome,non-related serious illness or drug abuse.

The study design is parallel, double blind, placebo and activecontrolled. Patients obtain treatment for 14 days with once dailyadministration of either 0.5 mg mirtazapine, 1.5 mg mirtazapine, 4.5 mgmirtazapine, 20 mg temazepam or placebo. Observations, assessments andmeasurements are recorded starting with one placebo treatment week(wash-out) before the start of the treatment and ending with one placebotreatment week after the treatment to assess rebound/withdrawal.

Assessment methods are poly-somnography (PSG) recordings for the nightsof day −2, −1, 1, 13, 14, 15, whereby night −1 is defined to be thenight immediately before the first day of the treatment. Subjectiveratings with rating scales for sleep and daytime functions (Leeds sleepevaluation questionnaire, MOS sleep rating scale, clinical globalimpression scale, Bastani mood rating scale, Lader Bond mood ratingscale, profile of mood states) are performed with evening and morningquestionnaires throughout the study period. Psychometric assessments areperformed on the mornings of day 1, 2 and day 15, whereby day 1 isdefined to be the first day on which drug or placebo is administered inthe evening. Blood is drawn on the mornings of day 1 and day 15 and onthe evening of day 15 and assessments are made with recording of vitalsigns and physical examination and laboratory determinations. Theimprovement of the quality, including efficacy of sleep and the safety,adverse effects and occurrence of rebound/withdrawal effects of thetreatment with drugs is observed in the changes before and aftertreatment of the various parameters measured with the indicated methods.Specifically the PSG assessments and subjective and objective assessmentof sleep and performance the morning after, reveal information on sleepparameters, such as the functional EEG characteristics, the time fallingasleep, total sleep time, the frequency and duration of night timeawakenings, the time of early morning awakening, fragmentation of sleep,the sensitivity for disruptive stimuli, the feelings of refreshment,restlessness or tiredness after awakening, the sense of balance andco-ordination upon getting up, the sleep hygiene during day time (suchas the occurrence of day time naps), the state of performance duringdaytime reflected in feeling tired, trouble in staying awake during theday, performance in cognitive tests such as simple reaction time, digitvigilance task, choice reaction time, rapid visual informationprocessing, tracking, numeric working memory, word recognition, anddaytime feelings of depressed mood, anxiety, confusion, anger,irritability and hangover effects. The Lader Bond mood rating scaleprovides daytime assessments separately along the dimensionsalert/drowsy, calm/excited, strong/feeble, muzzy/clear-headed,well-co-ordinated/clumsy, lethargic/energetic, contented/discontented,troubled/tranquil, mentally slow/quick witted, tense/relaxed,attentive/dreamy, incompetent/proficient, happy/sad,antagonistic/amicable, interested/bored, withdrawn/gregarious,worried/carefree, depressed/elated and self-centered/outward-going. TheBastani visual analogue scale provides daytime assessments separately ofthe feelings sleepy, nauseated, dizzy, calm, active, anxious, irritable,depressed, good overall, restless, strange, aroused and mellow.

1. A method of treatment of primary insomnia in a subject, comprising:administering an effective amount of mirtazapine to said subject,wherein the range of the amount is more than 0.1 to less than 5 mgmirtazapine or a pharmaceutically acceptable salt thereof.
 2. The methodof treatment according to claim 1, wherein mirtazapine is the Senantiomer.
 3. A method of treatment of transient sleep disorder in asubject, comprising: administering an effective amount of more than 0.1mg to about 4.5 mg of mirtazapine or a pharmaceutically acceptable saltthereof.
 4. The method of treatment according to claim 3, whereinmirtazapine is the S enantiomer.
 5. The method of treatment according toclaim 1, wherein the range of the amount is more than 0.1 to about 4.5mg mirtazapine.
 6. The method of treatment according to claim 5, whereinthe range of the amount is about 0.5 to about 4.5 mg mirtazapine.
 7. Themethod of treatment according to claim 3, wherein the range of theamount is more than 0.5 to about 4.5 mg mirtazapine.
 8. A method oftreatment of secondary insomnia in a subject, comprising: administeringan effective amount of more than 0.1 mg to about 4.5 mg of mirtazapineor a pharmaceutically acceptable salt thereof.
 9. The method oftreatment according to claim 8, wherein mirtazapine is the S enantiomer.10. The method of treatment according to claim 8, wherein the range ofthe amount is about 0.5 to about 4.5 mg mirtazapine.